JP7466927B2 - アンジェルマン症候群及び自閉症を治療するためのigf―2受容体作動剤リガンドの使用 - Google Patents
アンジェルマン症候群及び自閉症を治療するためのigf―2受容体作動剤リガンドの使用 Download PDFInfo
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Description
グラフの上部に実験スケジュールを示す。すべての実験において、マウスは、訓練又は試験のどちらかの20分前に、ビヒクル又はIGF-2のどちらかを皮下注射(↑)された。データはすべて、平均±標準誤差として表される。N=8~12/群。二元配置分散分析(ANOVA)後に、ボンフェローニ事後検定。*P<0.05、**P<0.01、***P<0.001
(A)ビヒクル又はIGF-2を注射された、対照として役立つ正常マウス(野生型、WT)、及びUbe3a-/+マウス(ASのマウスモデル)に関する、文脈的恐怖条件づけ訓練の間のショック伝達より前(Pre-US)又は後(Post-US)、及び訓練後24時間時の試験(試験)における、すくんでいる時間のパーセンテージ。
(B)訓練の20分前にビヒクル又はIGF-2を注射したWT及びUbe3a-/+マウスについて、訓練後4時間及び24時間目に試験した、新奇物体認識中の、見慣れた物体と比べた新奇物体への探索嗜好性パーセント。
(C)試験の20分前にビヒクル又はIGF-2を注射したWT及びUbe3a-/+マウスの、Y字型迷路における正しい交替のパーセント(正しい%)。
(D)試験の20分前にビヒクル又はIGF-2を注射したWT及びUbe3a-/+マウスが、回転ロッドから落下するまでの潜在時間、3日及び7日後に再び試験を行った。
(E)試験の20分前にビヒクル又はIGF-2を注射したWT及びUbe3a-/+マウスが、ビー玉を埋めるのに費やす時間。
(F)試験の20分前にビヒクル又はIGF-2を注射した後、WT及びUbe3a-/+マウスがオープンフィールドの中心に滞在した時間。
各セットにおける棒グラフは、左から右に、WTビヒクル、WT IGF-2、Ube3a-/+ビヒクル、及びUbe3a-/+IGF-2である。
訓練されていない(無処置と称する)8週齢のUbe3a-/+マウス及びWT同腹子から採取した全海馬タンパク質抽出物のウエスタンブロット解析。各相対値は、同じブロットで検出されたβ-アクチン(ローディングコントロールとして使用)に対して正規化された。すべてのデータは、平均±標準誤差として表され、WT無処置マウスの平均値に対して正規化された。N=4/群。独立t検定 *P<0.05、**P<0.01
無処置(訓練されていない対照)8週齢のUbe3a-/+マウス及びWT同腹子のmPFCから採取した全海馬タンパク質抽出物のウエスタンブロット解析。各相対値は、同じブロットで検出されたβ-アクチン(ローディングコントロールとして使用)に対して正規化された。すべてのデータは、平均±標準誤差として表され、WT無処置マウスの平均値に対して正規化された。N=4/群。独立t検定 *P<0.05、**P<0.01
グラフの上部に実験スケジュールを示す。データは、平均±標準誤差として表される。N=4/群。一元配置分散分析(ANOVA)後に、ボンフェローニ事後検定。*P<0.05、**P<0.01。WTマウスに、nORの訓練の20分前に、異なる用量のIGF2R.L1(L1)を皮下注射した。グラフは、訓練後4時間目及び24時間目に行われた試験における、見慣れた物体と比較した新奇物体に対する探索嗜好性のパーセントを示す。
グラフの上部に実験スケジュールを示す。すべての実験において、マウスは、訓練又は試験のどちらかの20分前に、ビヒクル又は850μg/kgのM6P(IGF-2R.L1あるいはL1)のどちらかを皮下注射(↑)された。
(A)訓練の20分前にビヒクル又はIGF-2R.L1を注射したWT(対照)及びUbe3a-/+(AS)マウスについて、訓練後4時間及び24時間目に試験した、nORパラダイムの間の、見慣れた物体と比較した新奇物体に対する探索嗜好性パーセント。N=4/群。データは、平均±標準誤差として表される。二元配置分散分析(ANOVA)後に、ボンフェローニ事後検定。*P<0.05、**P<0.01、***P<0.001
(B)試験前にビヒクル又はM6Pを注射したWT及びASマウスの、Y字型迷路における正しい交替のパーセント(正しい%)。データは、平均(±標準誤差)として表される。
(C)試験前にビヒクル又はIGF-2R.L1を注射したWT及びASマウスの、後肢クラスピング(Hindlimb Clasping)スコア。後肢クラスピングスコアは、以下のように測定し、表す;複数の後肢を一貫して、腹部から離れる方向である外側に伸ばす場合、スコア0とする。ぶら下げた時間の50%より多く、後肢の一本を腹部の方に縮める場合、スコア1とする。ぶら下げた時間の50%より多く、両方の後肢を腹部の方にある程度縮める場合、スコア2とする。ぶら下げた時間の50%より多く、複数の後肢を完全に縮めて腹部に触れさせる場合、スコア3とする。データはスコアで表される。B及びC: N=8~14/群。二元配置分散分析(ANOVA)後、チューキー事後検定。*P<0.05、**P<0.01、***P<0.001
グラフの上部に実験スケジュールを示す。すべての実験において、マウスは、訓練又は試験のどちらかの20分前に、ビヒクル、又は、850μg/kgのIGF-2R.L2(あるいはL2)と呼ばれるホスホネート-M6P(PnM6P)のどちらかを皮下注射(↑)された。
(A)訓練前にビヒクル又はL2を注射したWT(対照)及びUbe3a-/+(AS)マウスについて、訓練後4時間、24時間、及び5日目(5d)に試験した、nORパラダイムの間の、見慣れた物体と比較した新奇物体に対する探索嗜好性パーセント。N=4/群。データは、%平均±標準誤差として表される。
(B)試験の20分前にビヒクル又はL2を注射したWT(対照)及びASマウスが、回転ロッドから落下するまでの潜在時間(試験1)、2日後に再び試験を行った(試験2)。データは秒(s)で表される。
(C)試験前にビヒクル又はL2を注射したWT及びASマウスの、後肢クラスピングスコア。B及びC:N=3~4/群。データは後肢スコアで表される。二元配置分散分析(ANOVA)後、ボンフェローニ事後検定。*P<0.05、**P<0.01、***P<0.001
使用したマウスモデル
マウスは、父性インプリンティングUbe3A(ユビキチンタンパク質リガーゼE3A)ノックアウト変異を保有する変異雄マウス(B6.129S7-Ube3atm1Alb/J)(Jackson labs www.jax.orgから注文;ストックNo.016590)を、C57BL/6J雌正常マウスと交配することによって得た。雌のヘテロ接合性マウスを雄のC57BL/6Jマウスと交配させた;この交配からの子孫は、ヘテロ接合性の雄(母系伝達)、ヘテロ接合性の雌(母系伝達)、野生型の雄、野生型の雌である。これらの子孫を行動学的及び生化学的研究に用いた。これらのマウスは本明細書においてマウスと呼ばれ、それらの正常同腹仔は野生型(WT)マウス又は対照マウスと呼ばれる。
行動手順を開始する20分前に、IGF-2又はビヒクル対照溶液を皮下(s.c.)注射
成体ASマウスとWT同腹仔において、学習と記憶と実行機能に重要な2つの脳領域である、背側海馬(dHC)と内側前頭前皮質(mPFC)における、基本条件下(ホームケージに残存)でのタンパク質レベルを比較するために、ウェスタンブロット解析を行った。我々は、背側海馬(dHC)と内側前頭前皮質(mPFC)におけるグルコース代謝、可塑性、抑制性ニューロン機能、及びIGF-2経路に重要なマーカーのクラスについて有意な変化のエビデンスを見出した。具体的には、AS及びWT同腹仔における全タンパク質及びシナプトニューロソーム(シナプトノイロゾーム:シナプス画分)抽出物を評価し、以下の発現量を比較した:
i)IGF-2及びIGF-2R、ii)mTOR及びホスホ-mTOR、ULK-1及びホスホ-ULK-1、iii)興奮性ニューロン可塑性(Arc/Arg3.1、GluA1、GluA2)、iv)抑制性ニューロンマーカー(GAD67)、及び、v)グルコース/エネルギー代謝(LDHB、MCT1、MCT4、MCT2、GLUT1、GLUT3、pAMPK)である。
本実施例は、マンノース-6-リン酸(M6P)の全身投与が、アンジェルマン症候群マウスモデルにおける記憶欠損を逆転させることを実証する。我々は最初に、正常マウスの記憶増強に対する効果について、異なるM6P濃度を試験した。結果を図4に示す。IGF2R.L1は、M6Pである。
IGF-2R.L2(又はL2)と呼ばれる修飾M6P:ホスホネート-M6P(PnM6P)を試験した。図6に示すように、850μg/kgで注射されたL2は、nORにおけるASマウスの欠損を有意に逆転させ、訓練後4時間でWTマウスにおけるnOR記憶保持を有意に増強した(図6A)。訓練の24時間後に、L2を注射したWTマウス及びASマウスの両方が、ビヒクル注射群と比較して有意な記憶を示した。訓練後5日目で再検査した場合(5d試験)、いずれの群(ビヒクル又はL2注射)も有意な記憶を示さなかったが、WT対照は記憶増強の強い傾向を示し、これは群あたりより多くの数の被験体が含まれる場合に有意になり得る。
本実施例は、M6P誘導体の合成及び特性決定を記載する。
多重度は以下のように略される:s(一重線); d(二重線); t(三重線); q(四重線); quint(五重線); sext(六重線); hept(七重線); br(幅広線); m(多重線);あるいはそれらの組み合わせ。高分解能質量分析(HRMS)は、大気圧化学イオン化(APCI)方法又はエレクトロスプレーイオン化(ESI)方法のいずれかと組み合わせて、Agilent 6224 Accurate-Mass time-of-flight(TOF)液体クロマトグラフィー質量分析計(LC/MS)を用いて行った。フーリエ変換赤外(FT-IR)スペクトルを、ポリスチレン標準を参照するThermo Scientific Nicolet 6700 FT-IRスペクトロメータで記録した。シグナルは、w(弱い);m(中程度);s(強い)、br(広い)と略される記述子を伴い波数(cm-1)での吸収振動数として報告される。高速液体クロマトグラフィー(HPLC)精製を、逆相(RP)Phenomenex Semipreparativeカラム(00D-4439-E0 Gemini、C18相、3μm粒径、110Å細孔径)を有するAgilent 1260 Infinity II LCで、8mL/分の流速で、及び(A)アセトニトリル(HPLCグレード)と(B)水(HPLCグレード)中の0.1%ギ酸(FA)の溶媒混合物を用いて行った。旋光度測定は、Flint Glass Faraday細胞モジュレータ、ナトリウムランプ光源、及び光電子増倍管(PMT)検出器を備えたJasco P-2000旋光計で記録した。比旋光度は、式[α]=(100・α)/(l・c)に基づいて計算し、ここで、濃度cはg/100ml単位であり、経路長lはデシメートル単位である。計算された比旋光度は単位なしの値として報告され、[α]D T比旋光度(c、濃度、溶媒)として表され、ここで、温度Tは℃単位であり、Dは、ナトリウムD線モニタ波長(589nm)を表す。
1H NMR (400 MHz, CDCl3) δ 7.48 - 7.28 (15H, m), 4.72 (1H, d, J=1.6 Hz), 3.92 (1H, m), 3.82 - 3.63 (3H, m), 3.50 - 3.39 (2H, m), 3.38 (3H, s), 2.73 (1H, m), 2.54 (1H, m), 2.27 (1H, m). 13C NMR (101 MHz, CDCl3) δ 143.9, 128.9, 128.3, 127.5, 100.9, 87.7, 72.0, 70.64, 70.59, 70.1, 65.2, 55.3.
1H NMR (CDCl3, 400 MHz) δ 7.41 - 7.30 (15H, m), 4.97 (1H, d, J=10.9 Hz), 4.81 (1H, d, J=12.3 Hz), 4.75 - 4.65 (5H, m), 3.99 (1H, app. t, J=9.4 Hz), 3.92 (1H, dd, J=9.4, 2.9 Hz), 3.90 - 3.84 (1H, m), 3.83 - 3.76 (2H, m), 3.68 - 3.62 (1H, m), 3.33 (3H, s), 2.00 (1H, app. t, J=6.4 Hz). 13C NMR (101 MHz, CDCl3) δ 138.8, 138.7, 138.6, 128.70, 128.68, 128.67, 128.3, 128.1, 128.0, 127.9, 99.6, 80.5, 75.5, 75.2, 75.0, 73.2, 72.5, 72.4, 62.7, 55.1. HRMS (APCI/LC-TOF) m/z: [M + NH4]+ C28H32O6の計算値:482.2537; 実測値:482.2533
[α]D 20=+40.4 (c=1.01, CHCl3). 1H NMR (CDCl3, 400 MHz) δ 7.39 - 7.27 (15H, m), 6.96 (1H, ddd, J=22.1, 17.2, 4.3 Hz), 6.12 (1H, ddd, J=21.2, 17.5, 1.8 Hz), 4.88 及び 4.59 (2H, AMq, J=10.6 Hz), 4.77 及び 4.70 (2H, ABq, J=12.4 Hz), 4.73 (1H, s), 4.63 (2H, s), 4.14 - 4.03 (5H, m), 3.90 (1H, dd, J=9.3, 3.0 Hz), 3.81 - 3.77 (1H, m), 3.72 (1H, t, J=9.5 Hz), 3.29 (3H, s), 1.31 (6H, t, J=7.1 Hz). 13C NMR (CDCl3, 101 MHz) δ 148.4 (d, J=5.8 Hz), 138.7, 138.5, 138.3, 128.7, 128.4, 128.14, 128.05, 127.9, 118.3 (d, J=188.2 Hz), 99.6, 80.4, 78.5 (d, J=1.9 Hz), 75.7, 75.0, 73.2, 72.7, 71.5 (d, J=21.5 Hz), 62.1 (dd, J=5.8, 1.3 Hz), 55.3, 16.7. 31P NMR (162 MHz, CDCl3) δ 18.3. FT-IR (neat, cm-1): ν(C-H)=2982 (m), ν(P=O)=1253 (s), ν(P-O-C)=1024 (s), ν(P-O-C)=969 (m).
TLC (EtOH/EtOAc/ヘキサン 1.5:1.5:7): Rf=0.49. 1H NMR (CDCl3, 400 MHz) δ 7.40 - 7.29 (15H, m), 7.10 (1H, ddd, J=24.5, 17.2, 3.8 Hz), 6.40 - 6.17 (1H, m), 5.80 - 5.65 (6H, m), 4.81 - 4.59 (7H, m), 4.22 - 4.14 (1H, m), 3.91 (1H, dd, J=9.3, 3.1 Hz), 3.83 - 3.78 (1H, m), 3.74 (1H, t, J=9.5 Hz), 3.30 (3H, s), 1.32 - 1.29 (12H, m). 13C NMR (CDCl3, 101 MHz) δ 153.5, 138.7, 138.5, 138.3, 128.8, 128.7, 128.6, 128.2, 128.1, 127.9, 99.7, 84.5 (d, J=5.7 Hz), 84.4 (d, J=6.8 Hz), 80.5, 78.3 (d, J=2.1 Hz), 75.8, 75.0, 73.5 (d, J=3.5 Hz), 73.3, 72.7, 71.3 (d, J=22.3 Hz), 55.3. 31P NMR (162 MHz, CDCl3) δ 26.3.
1H NMR (400 MHz, CDCl3) δ 5.68 (2H, dd, J=20.5 Hz, J=5.3 Hz, H8), 5.65 (2H, dd, J=18.3 Hz, J=5.4 Hz, H8’), 4.93 (2H, hept, J=6.3 Hz, H10) , 4.68 (1H, s, H1), 3.95 - 3.86 (1H, br, H5), 3.74 (1H, m, H2), 3.58 (2H, m, H3, H4), 3.35 (3H, s, OCH 3 ), 3.22 - 3.07 (1H, m, OH), 2.95 (2H, m, 2×OH), 2.27 - 2.07 (2H, m), 2.06 - 1.86 (2H, m, H6, H6’, H7, H7’), 1.32 (12H, d, J=6.2 Hz, H11). 13C NMR (101 MHz, CDCl3) δ 153.6 (d, J=3.7 Hz, C9), 101.2 (s, C1), 84.5 (d, J=6.3 Hz, C8), 84.3 (d, J=6.3 Hz, C8’), 73.7 (d, J=3.2Hz, C10), 72.0 (s, C2), 70.9 (d, J=16.1 Hz, C5), 70.6 (s), 70.5 (s, C3, C4), 55.3 (s, OCH3), 23.8 (d, J=4.5 Hz, C6), 22.4 (s, C11), 21.7 (d, J=142.3 Hz, C7). 31P NMR (162 MHz, CDCl3) δ 34.4. FT-IR (neat, cm-1): ν(O-H)=3409 (br), ν(C-H)=2923 (m), ν(C=O)=1760 (s), ν(P=O)=1269 (s). LR-MS (ESI-) [M+HCOO]-の計算値:549.2; 実測値:549.2.
Claims (17)
- 前記NDの治療が、
(i)発話、知的能力、動作、及び社会的行動における発達遅延の1つ以上;及び/又は
(ii)てんかん
を軽減することを含む、請求項1に記載の組成物。 - M6P又はその薬学的に許容される塩を含む、請求項1又は2に記載の組成物。
- MP6を含む、請求項1又は2に記載の組成物。
- M6P又はその薬学的に許容される塩が、体重1kgあたり1~2,000μgの範囲の量で被験体に投与される、請求項3又は4に記載の組成物。
- M6P又はその薬学的に許容される塩が、別の成分にコンジュゲートされていない、請求項3又は4に記載の組成物。
- 前記組成物において、M6P又はその薬学的に許容される塩が、IGF-2受容体に特異的に結合する唯一の薬剤である、請求項3又は4に記載の組成物。
- L2又はその薬学的に許容される塩が、体重1kgあたり1~2,000μgの範囲の量で被験体に投与される、請求項5又は6に記載の組成物。
- L2又はその薬学的に許容される塩が、体重1kgあたり1~500μgの範囲の量で被験体に投与される、請求項10に記載の組成物。
- L2が、別の成分にコンジュゲートされていない、請求項5又は6に記載の組成物。
- 前記組成物において、L2が、IGF-2受容体に特異的に結合する唯一の薬剤である、請求項5又は6に記載の組成物。
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GB9516012D0 (en) | 1995-08-04 | 1995-10-04 | Univ Manchester | Pharmaceutical composition |
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AUPO309896A0 (en) * | 1996-10-18 | 1996-11-14 | Australian National University, The | Novel phosphosugars and phosphosugar-containing compounds having anti-inflammatory activity |
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Non-Patent Citations (3)
Title |
---|
Gary-Bobo, M. et al.,Mannose 6-phosphate receptor targeting and its applications in human diseases,Current Medicinal Chemistry,2007年,Vol.14, No.28,p.2945-2953,doi:10.2174/092986707782794005 |
Steinmetz, A. B. et al.,Insulin-Like Growth Factor II Targets the mTOR Pathway to Reverse Autism-Like Phenotypes in Mice,The Journal of Neuroscience,2018年01月24日,Vol.38, No.4,p.1015-1029,doi:10.1523/JNEUROSCI.2010-17.2017 |
Vidal, S. et al.,Synthesis and biological evaluation of new mannose 6-phosphate analogues,Bioorganic & Medicinal Chemistry,2002年,Vol.10, No.12,p.4051-4056,doi:10.1016/s0968-0896(02)00264-x |
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CN113164501A (zh) | 2021-07-23 |
PL3833358T3 (pl) | 2024-03-04 |
EP3833358B1 (en) | 2023-12-06 |
WO2020033971A1 (en) | 2020-02-13 |
EP4356964A2 (en) | 2024-04-24 |
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